PROJECT SUMMARY Type 1 diabetes (T1D) is a disease of increasing prevalence worldwide. Despite decades of research, the specific underlying causes and consistently effective methods to prevent or cure the disease have not been identified. Much of this research has involved rodent models of the disease, particularly the non-obese diabetic mouse; however it has become evident that this model has substantial limitations. A large animal model more reflective of the human disease could provide important translational discoveries in the areas of pathogenesis, prevention, and therapy of T1D. Canine diabetes is similar in many ways to human T1D; however, in-depth studies characterizing the phenotypic and etiopathologic characteristics are lacking. The genetic structure of dog breeds, living environment that is similar to humans, and disease heterogeneity also contribute to the attractiveness of the dog as a potential disease model. The overall objective of this proposal is to examine the etiopathogenesis of canine diabetes to determine the relevance of these animals as a naturally occurring model of human T1D. This objective will be evaluated via the following specific aims: 1) Define the phenotypic characteristics of canine diabetes from initial onset to established disease, 2) Evaluate the role of autoimmunity in the pathogenesis of canine diabetes, and 3) Identify potential biomarkers of the pre-diabetic state in dogs. To accomplish these aims, newly diagnosed diabetic dogs will be recruited to evaluate ? cell function, metabolomic profiles, and to detect evidence of autoimmunity using novel methodology. Additionally, a cohort of non-diabetic dogs will be followed and monitored for the development of diabetes to search for biomarkers of a pre-diabetic state. The principle investigator, Dr. Allison O?Kell, is a veterinarian with board certification in small animal internal medicine and is an Assistant Professor at the University of Florida College of Veterinary Medicine. Together with her mentor?s laboratory, she has performed preliminary studies supportive of the aims of this proposal. This career development award will provide Dr. O?Kell with the additional training needed to achieve her goal of becoming an independent investigator, which includes training in the areas of: 1) prospective clinical study design and implementation, 2) performance, interpretation, and evaluation of various laboratory techniques and diagnostic tests, 3) statistical methods and interpretation, 4) collaboration with a multi- disciplinary and multi-institutional team, and 5) grant and manuscript writing. Dr. O?Kell has developed a comprehensive program including didactic training, practical and laboratory experience, and a strong mentoring and advisory team. The University of Florida Diabetes Institute and College of Veterinary Medicine together will provide a collegial and supportive environment with the equipment, laboratory space, and resources necessary to complete the research and training. At the culmination of this proposal, Dr. O?Kell will be poised to achieve independence as a researcher with continuing investigation in the field of diabetes.